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Adenosine and guanosine-based oligonucleotides-loaded PLGA nanoparticles attenuates progression of surgically induced
Yoonhee Kim1,2, Jin Han1,2,3, Ji Young Park1,4
1Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu, Republic of Korea.
Abstract:
Osteoarthritis (OA) is a chronic degenerative joint disease that lacks effective therapies to halt its progression. While endogenous purinergic signaling-particularly via adenosine-shows promise for reducing inflammation, it is limited by short half-life and off-target effects. To address these limitations, we developed an optimal anti-inflammatory adenosine-guanosine-based oligonucleotide encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NanoOligo) to enhance in vivo stability and investigated its impact on surgically induced OA models and the underlying mechanisms responsible for its anabolic effects. A large oligonucleotide library (482 unique 10- to 20-mer sequences) was screened in RAW264.7 macrophages under LPS-induced inflammation to identify the most potent candidate, which was then encapsulated into PLGA nanoparticles using a microfluidic system. NanoOligo significantly protected against cartilage degeneration and alleviated pain behaviors in the rat ACLT + pMx model following intra-articular administration. In IL-1β-treated chondrocytes, it markedly suppressed inflammatory cytokines (TNFα, IL-6) and catabolic proteases (MMP-3, MMP-13, ADAMTS5). Mechanistically, NanoOligo's anti-catabolic effects were dependent on A1R and A2AR, leading to activation of the PKA-CREB axis and suppression of p38 MAPK signaling, which in turn reduced oxidative stress and cellular senescence via upregulation of the Sirt1-Nrf2-HO-1 antioxidant pathway. Collectively, these findings support joint-localized purinergic modulation as a potential therapeutic target for OA treatment, aligning structural protection with improvements in pain-related behaviors.
Insights
A novel nanoparticle-delivered oligonucleotide (NanoOligo) effectively treats osteoarthritis (OA) by reducing inflammation and protecting cartilage. This breakthrough offers new hope for managing OA pain and degeneration.
Area of Science:
- Biochemistry
- Pharmacology
- Biotechnology
Background:
- Osteoarthritis (OA) is a degenerative joint disease with limited therapeutic options.
- Endogenous purinergic signaling, particularly adenosine, shows anti-inflammatory potential but suffers from instability and off-target effects.
- Developing stable, targeted therapies is crucial for effective OA treatment.
Purpose of the Study:
- To develop and evaluate an adenosine-guanosine-based oligonucleotide encapsulated in nanoparticles (NanoOligo) for enhanced stability and efficacy in OA.
- To investigate the therapeutic impact of NanoOligo on surgically induced OA models and elucidate its underlying anabolic mechanisms.
Main Methods:
- Screening of an oligonucleotide library in macrophages to identify potent anti-inflammatory sequences.
- Encapsulation of the lead oligonucleotide into poly(lactic-co-glycolic) acid (PLGA) nanoparticles using microfluidics.
- Evaluation of NanoOligo in rat surgical OA models (ACLT + pMx) and IL-1β-treated chondrocytes.
Main Results:
- NanoOligo significantly protected against cartilage degeneration and reduced pain behaviors in vivo.
- It suppressed key inflammatory cytokines (TNFα, IL-6) and catabolic proteases (MMP-3, MMP-13, ADAMTS5) in chondrocytes.
- Mechanistic studies revealed NanoOligo activates A1R/A2AR, PKA-CREB, and the Sirt1-Nrf2-HO-1 antioxidant pathway, while suppressing p38 MAPK.
Conclusions:
- Joint-localized purinergic modulation using NanoOligo represents a promising therapeutic strategy for osteoarthritis.
- The findings support NanoOligo's ability to simultaneously promote structural protection and alleviate OA-related pain.
- This approach addresses the limitations of current OA therapies by enhancing drug stability and targeting inflammatory pathways.
